Midas touch at the nano-bio interface: Size-dependent attenuation of parathyroid hormone signaling by gold...

Peptide hormone signaling is increasingly recognized as a target for nanomaterial-mediated modulation, yet how nanoparticle size governs nano-peptide interfacial interactions remain poorly understood. Here, gold nanoparticles (AuNPs) of controlled diameters (15-80 nm) were screened for their capacity to modulate parathyroid hormone (PTH) activity. A clear size-dependent effect was identified: 35 nm AuNPs most effectively attenuated PTH-induced receptor activator of nuclear factor κB ligand (RANKL) expression and cyclic adenosine monophosphate (cAMP) signaling in vitro. Transcriptomic profiling revealed broad downregulation of PTH-downstream pathways. Molecular docking further suggested that AuNPs destabilized the PTH/ PTH receptor-1 (PTH1R) complex. In an adeno-associated virus (AAV)-driven PTH-overexpression mouse model, 35 nm AuNP treatment significantly normalized mineral homeostasis, improved trabecular microarchitecture, and reduced serum uric acid levels without detectable organ toxicity. These findings support a working model in which nanoparticle size serves as a tunable parameter modulating peptide hormone bioavailability at the extracellular nano-bio interface.